Use of vibration in composite fixation

ABSTRACT

Methods of employing bone defect filling, e.g., orthopedic cements, in conjunction with hard tissue securing devices, e.g., screws, plates or rods, are provided. A feature of the subject methods is that the cement is introduced to a target bone site through a passageway of the securing device while a vibratory force is applied to the securing device. Also provided are systems and kits that find use in practicing the subject methods. The subject methods, devices and systems find use in a variety of different applications.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.10/900,019 filed on Jul. 26, 2004; which application is acontinuation-in-part of application Ser. No. 10/797,907 filed on Mar. 9,2004; the disclosures of which are herein incorporated by reference.

INTRODUCTION

Background

Orthopedic/bone defect filling cements find use in a variety ofdifferent applications, including orthopedic and dental applications. Amultitude of different orthopedic cements have been developed to date,where such cements include both polymeric based cements, such as PMMA,as well as mineral based cements, e.g., calcium and/or phosphatecontaining cements. As the field matures, ever more chemicalformulations and applications are being developed in which orthopediccements find use.

While the field of orthopedic/bone defect filling cements has progressedgreatly, there continues to be a need for improvements in this area.Where the target bone site is a porous cancellous structure, e.g., asmay be encountered in a reduced fracture or inside a compromisedvertebral body, one approach is to deliver the cement under highpressure, so that it adequately penetrates the cancellous bone tissue.However, a disadvantage of high-pressure delivery methods is that theycan result in penetration beyond the site of interest, and delivery maybe hard to control, such that even when the pressure source is removed,cement still penetrates the tissue, perhaps to undesirable areas and/orcausing undesirable side effects. Specifically, pressurization of cementin the body often causes emboli of cement or fat which can result indeath of the patient or other adverse events.

An alternative to delivery under pressure is to remove the cancelloustissue from the target site to produce a true void space into which thecement composition may be introduced. In certain embodiments, a voidspace may be produced by introducing a balloon into the target site andexpanding the balloon in a manner that compresses the cancellous tissueand results in the production of a void space at the target site.However, there are disadvantages to this approach as well, such as theloss of cancellous tissue. Furthermore, the expansion of the balloon cancause fat emboli that can result in patient death or adverse events.

As such, there continues to be an interest in the development of newprotocols and devices for use in applications where such cements areemployed.

RELEVANT LITERATURE

United States Patents of interest include: U.S. Pat. Nos. 6,375,935;6,139,578; 6,027,742; 6,005,162; 5,997,624; 5,976,234; 5,968,253;5,962,028; 5,954,867; 5,900,254; 5,697,981; 5,695,729; 5,679,294;5,580,623; 5,545,254; 5,525,148; 5,281,265; 4,990,163; 4,497,075;4,429,691; 4,161,511 and 4,160,012. Also of interest is published UnitedStates Application No. 2004/0024410 A1. See also Baroud et al.,“Influence of Oscillatory Mixing on the Injectability of Three Acrylicand Two Calcium-Phosphate Bone Cements for Vertebroplasty,” J.Biomedical Materials Research, Part B-Applied Biomaterials; (Jan. 15,2004); v. 68B, no. 1, p. 105-111.

SUMMARY OF THE INVENTION

Methods of employing bone defect filling, e.g., orthopedic cements, inconjunction with hard tissue securing devices, e.g., screws, plates orrods, to obtain composite fixation are provided. A feature of thesubject methods is that the cement is introduced to a target bone sitethrough a passageway of the securing device while a vibratory force isapplied to the securing device. Also provided are systems and kits thatfind use in practicing the subject methods. The subject methods, devicesand systems find use in a variety of different applications.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1 to 6 provide various views of a pneumatically driven needlevibrating device that may be employed in certain embodiments of thesubject invention, e.g., where vibration is indicated applied to acannulated hard tissue securing device by applying vibration directlythe delivery device while the device is jointed to the cannulation ofthe securing device.

FIG. 7 provides a view of an alternatively pneumatically driven cannulavibrating device that may be employed in certain embodiments of thesubject invention.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

Methods of employing bone defect filling, e.g., orthopedic cements, inconjunction with hard tissue securing devices, e.g., screws, plates orrods, for composite fixation are provided. A feature of the subjectmethods is that the cement is introduced to a target bone site through apassageway of the securing device while a vibratory force is applied tothe securing device. Also provided are systems and kits that find use inpracticing the subject methods. The subject methods, devices and systemsfind use in a variety of different applications.

Before the present invention is described in greater detail, it is to beunderstood that this invention is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, representativeillustrative methods and materials are now described.

All publications and patents cited in this specification are hereinincorporated by reference as if each individual publication or patentwere specifically and individually indicated to be incorporated byreference and are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention. Further, the dates ofpublication provided may be different from the actual publication dateswhich may need to be independently confirmed.

It is noted that, as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

In further describing the subject invention, the subject methods will bedescribed first, as well as representative utilities thereof, followedby a review of representative devices, systems and kits that may be usedtherein.

Methods

As summarized above, the subject methods are methods of delivering anorthopedic cement to a target bone site. A feature of the subjectmethods is that the cement is delivered to the target bone site througha passageway of a hard tissue securing device, e.g., a cannulation,while a vibratory force (i.e., vibration) is applied to the hard tissuesecuring device, either directly or indirectly. For purposes of clarityof description, representative hard tissue securing devices are reviewedfirst, followed by a review of representative orthopedic cements andthen a more detailed discussion of the subject methods.

Hard Tissue Securing Device

The phrase “hard tissue securing device” as used herein refers to anyhard tissue fixation element or structure that includes a passagewaythrough which an orthopedic cement may be moved. In representativeembodiments, hard tissue securing devices are devices that areconfigured to secure or fix two or more pieces of hard tissue, e.g.,bone, relative to each other such that the two or more pieces do notmove relative to each other. As is known in the art, such hard tissuesecuring or fixation devices have a variety of different configurations,where representative devices of interest include, but are not limitedto: screws, rods, plates, wires, external fixation devices, e.g., pins,and the like.

A feature of the hard tissue fixation devices employed in the subjectmethods is that they include a passageway, as mentioned above. By“passageway” is meant a flow path (e.g., channel, duct, bore, etc.)through or along which an orthopedic cement may pass. The passageway is,in representative embodiments, bounded on all sides, such that it isconfigured as an elongated member having an entrance and an exit. Thecross-sectional configuration of the flow path may vary significantly,and may be circular, oval, square, rectangular, or other shape,including irregular.

In representative embodiments, the internal passageway of the securingdevice is one that has a length which is longer that its width (e.g.,internal diameter), where the length may be at least about 1.5 timelonger, such as at least about 2 times longer, including at least about3 times longer, at least about 5 times longer, at least about 10 timeslonger, than the width of the passageway. In representative embodiments,the width (e.g., internal diameter) of the passageway ranges from about1 to about 20 mm, such as from about 1 to about 15 mm.

A given hard tissue securing device may include a single passageway, asdescribed above, or a plurality of such passageways, e.g., 2 or more, 3or more, 4 or more, etc. The passageway may be configured to have asingle inlet and exit, or multiple inlets and/or exits, as desired. Forexample, the end of the passage through which the composition flows outduring use may include multiple outlets or ports, so as to provide foreven introduction of cement to the target site from the end of thepassageway. In one representative embodiment, the passageway may befenestrated with multiple outlets at one end, e.g., to provide for broaddispersion of the cement around the end of the hardware element, e.g.,in the cancellous bone site. For example, a cannulated screw with afenestrated end may be employed in certain embodiments.

As indicated above, a variety of different hard tissue securing devicesmay be used in the subject methods. In representative embodiments, suchdevices may be devices that, in the art, are conveniently referred to ascannulated devices, in that they include a passageway as describedabove. In many such devices, the passageway is present in order toprovide for passage of the device over a guidewire during implantation,as is known in the art. This cannulation or passageway is thereforepresent in theses devices for another purpose, and is employed in thepresent invention as a delivery route for the cement to a cancellousbone target site. Representative hard tissue securing devices are nowreviewed in greater detail.

In representative embodiments, the hard tissue securing device is acannulated screw. A variety of different cannulated screws are known inthe art, where such devices are generally elongated structures thatinclude a threaded region, e.g., external threaded region and aninternal bore, e.g., dimensioned for passage of a guidewiretherethrough. Representative cannulated screws are disclosed in U.S.Pat. Nos. 6,635,059; 6,436,100; 6,270,501; 6,010,507; 6,004,321;5,425,733; 5,211,647; 5,129,901 and 4,950,270; the disclosures of whichwith respect to cannulated screws are specifically incorporated byreference. As is known in the art, the screw may have a variety ofdimensions and configurations, depending on its particular application.

Another type of cannulated hard tissue securing device of interest is acannulated nail. Like the cannulated screw, the cannulated nailgenerally is an elongated structure that includes an internal bore,e.g., for passing the nail over a guidewire. Cannulated nails, includingintermedullary or IM cannulated nails, are known in the art.Representative cannulated nails are disclosed in U.S. Pat. Nos.6,783,529; 6,648,889; 6,547,791; 5,690,842; 5,645,545; 5,268,000;4,846,162 and 4,103,683; the disclosures of which with respect tocannulated nails are specifically incorporated by reference. As is knownin the art, the nail may have a variety of dimensions andconfigurations, depending on its particular application.

Another type of cannulated hard tissue securing device of interest is acannulated rod. Like the cannulated nail, the cannulated rod generallyis an elongated structure that includes an internal bore. Cannulatedrods, including intermedullary or IM cannulated rods, are known in theart. Representative cannulated nails are disclosed in U.S. Pat. Nos.5,562,667 and 5,643,321; the disclosures of which with respect tocannulated rods are specifically incorporated by reference. As is knownin the art, the rod may have a variety of dimensions and configurations,depending on its particular application.

Yet another representative hard tissue securing device of interest is acannulated plate. Such plates include a passageway or cannulation, e.g.,for use during implantation where the plate is passed over a guidewire.A representative type of cannulated plate of interest is a cannulatedblade plate, such as the cannulated blade plates sold by Synthes (Paoli,Pa.). Cannulated blade plates are also described in Grant et al., Clin.Orthop. Relat. Res. 1990 October; (259):111-3; Chin et al., Clin OrthopRelat Res. 2003 April; (409):241-9; Fuchs et al., Zentralbl Chir. 2003January; 128 (1):22-7; and Morgan et al., Foot Ankle Int. 1999 June; 20(6):375-8. As is known in the art, the plate may have a variety ofdimensions and configurations, depending on its particular application.

Yet another representative type of hard tissue securing device ofinterest is an external fixation device, e.g., pins and the like, wheresuch structures are known in the art.

The above types of cannulated hard tissue securing devices arerepresentative of the different types of cannulated securing devicesthat are employed in the present invention.

Orthopedic Cements

As summarized above, a feature of the subject methods is that anorthopedic cement is delivered through the passageway of the hard tissuesecuring device. A wide variety of orthopedic (i.e., bone defectfilling) cements may be employed according to the subject invention.Representative cements include, but are not limited to: polymeric basedcements, e.g., polymethylmethacrylate (PMMA); composite cements (acryliccements in conjunction with ceramics); and calcium and/or phosphatebased cements (i.e., cements that include calcium and/or phosphateions), e.g., calcium sulfate (sulphate) cements; magnesium amoniumphosphate cements, calcium phosphate cements, cements containingradioopaque tracer particle that improve fluoroscopic visualization ofthe cement, etc. However, in certain embodiments of the subject methods,the orthopedic cement that is employed is one that has a specificgravity at 20° C. that is greater than about 1.0, such as greater thanabout 1.5, greater than about 2.0, including greater than about 2.5,e.g., greater than about 3.0 etc. In certain embodiments, the cementthat is employed is one that does not require or benefit from compactionfollowing delivery. Examples of cements that may require or benefit fromcompaction (and therefore are not employed in certain embodiments of thesubject invention) include polymeric cements, e.g., PMMA, as well asgranular type bone void filling products, such as the bone filling mediadescribed in United States Published Patent Application 2004/0024410.

Two representative types of cements that find use in the subjectinvention are polymeric cements and calcium phosphate cements, each ofwhich is now described in greater detail below.

Polymeric Cements

In certain embodiments, the bone cements that are delivered according tothe subject invention are polymeric materials which may include one ormore different types of polymers that, in preparation, undergo achemical reaction, e.g., a polymerization and/or cross-linking reaction,to produce a final product. The bone cements are, in representativeembodiments, prepared by combining a liquid monomer and a powderedcopolymer, such as methyl methacrylate and polymethyl methacrylate ormethyl methacrylate styrene. As used herein, the terms “(meth)acrylate”and “poly(meth)acrylate” include the monomers and polymers,respectively, of methacrylic acid esters and acrylic acid esters, andthe polymers also include the co-polymers of the compounds named.

In representative embodiments, the subject bone cement compositionincludes a solid finely divided powdery or granular polymer componentand a liquid reactive or polymerizable, e.g., monomer, component that isalso a solvent or swelling agent for the polymer component. The polymerand monomer components can be based on the acrylic, e.g., (meth)acrylatesystem, however, other polymeric systems can also be used. Forconvenience, the cement system may at times be broadly referred to as anacrylic polymer, or as based on PMMA (polymethylmethacrylate), arepresentative polymer component. While the invention is describedherein in terms of a representative embodiment, i.e., bone cement, it isto be understood that the invention is also directed to dental/toothcements.

More generally, the polymer component of the composition can be anymethyl(meth)acrylate polymer such as methyl(meth)acrylate homopolymersand copolymers of methyl(meth)acrylate with alpha, beta-ethylenicallyunsaturated compounds such as vinyl acetate, alkyl (e.g., C₂-C₆)(meth)acrylates and multi-functional acrylic monomers such as alkylenedimethacrylate and alkylene diacrylates and triacrylates. These polymersgenerally have a molecular weight between 500,000 and 2,000,000.Methylmethacrylate homopolymers and copolymers are preferred. Thereactive monomer component may be methyl acrylate or methyl methacrylatealthough the C₂-C₄ alkyl(meth)acrylates, such as ethyl(meth)acrylate,propyl(meth)acrylate or (n-, or iso-)butyl(meth)acrylate, can also beused.

These bone cement materials, which are themselves well known andcommercially available, are usually provided with 2 parts by weight ofthe finely divided polymer and 1 part by weight of liquid monomer,although higher or lower ratios can also be used, and are characterizedas being self-polymerizable substances which are mixed, together with apolymerization catalyst, such as dibenzoyl peroxide, and polymerizationaccelerator, such as dimethyl-p-toluidine, immediately prior to theoperation to form a viscous liquid or pasty mass.

Curing of the bone cement composition is typically accomplished by anysuitable initiator system such as from about 0.1 to about 3% by weight,such as about 0.6% of a conventional free radical initiator. Theinitiator can be a peroxy compound or an azo compound. For purposes ofbiocompatability benzoyl peroxide is a very suitable free radicalinitiator. The curing temperature is generally reduced to roomtemperature, e.g. about 25° to 30° C., by inclusion in the formulationof an activator for the peroxide catalyst which causes more rapiddecomposition of the peroxide to form free radicals. Suitable peroxidecatalysts include benzoyl peroxide, 2,4-dichlorobenzoyl peroxide and4-chlorobenzoyl peroxide. Activators or accelerators for these catalystsinclude N,N-dialkyl anilines or N,N-dialkyl toluidines generallyemployed in amounts ranging from about 0.1 to 1% based on the weight ofmonomer present. A representative activator isN,N-di(2-hydroxyethyl)-p-toluidine. In order to provide longer shelflife for the compositions of the invention, the composition may bestored in a closed container at cold temperature. Stabilizers, such ashydroquinone or chlorophyll may also be added to the monomer compound.

Bone cements containing both activator and peroxide are provided astwo-part compositions in which the activator and monomer and peroxideand polymer component may be packaged in separate containers. Theproportions by weight of polymer and liquid monomer can range from about4:1 to 1:2, preferably 3:1 to 1:1.5, such as 2:1, 1.5:1, 1:1 or 1:1.5.

Several representative cements are sold commercially and amenable foruse in the subject invention. Such commercially available cementsinclude, but are not limited to: the SIMPLEX™ bone cement(Howmedica-Stryker); the OTEOBOND™ bone cement (Zimmer); the CMW™ bonecement (Depuy); the ENDURANCE™ bone cement (Depuy); and the CORTOSS™bone cement (Orthovita).

In certain embodiments, the cements may include imaging or “tracer”elements, e.g., radioopaque or radioopacifier elements, which providefor enhanced imaging of the cement during delivery, e.g., as visualizedby radiographic imaging techniques. Representative radiopaque particlesthat may find use include radiopaque materials selected from a groupconsisting of barium sulfate, zirconium dioxide, tantalum, tungsten,platinum, gold, silver, stainless steel and titanium. Representativetracer elements and protocols for imaging the same are described in U.S.Pat. Nos. 6,309,420 and 6,273,916; the disclosures of which are hereinincorporated by reference.

Calcium Phosphate Cements

In certain embodiments, the cement that is employed is a calciumphosphate cement. A variety of calcium phosphate cements may bedelivered to a target site according to the subject invention.Representative cements of interest typically include dry reactants thatinclude a calcium source and a phosphate source that are combined with asetting fluid under conditions sufficient to produce a settable, e.g.,flowable or moldable, composition that sets into a calcium-phosphatecontaining product, sometimes even when immersed in a fluid environment.

The dry reactants may include a calcium source and a phosphate source.The dry reactants are typically particulate compositions, e.g., powders,where the particle size of the components of the particulatecompositions typically ranges from about 1 to about 1000 microns,usually from about 1 to about 200 microns and more usually from about 1to about 40 microns.

As mentioned above, the dry reactants may include a calcium source and aphosphate source. The calcium source and phosphate source may be presentas a single compound or present as two or more compounds. As such, asingle calcium phosphate present in the dry reactants may be the calciumsource and the phosphate source. Alternatively, two or more compoundsmay be present in the dry reactants, where the compounds may becompounds that include calcium, phosphate or calcium and phosphate.Calcium phosphate sources of interest that may be present in the dryreactants include: MCPM (monocalcium phosphate monohydrate orCa(H₂PO₄)₂.H₂O); DCPD (dicalcium phosphate dihydrate, brushite orCaHPO₄.2H₂O); ACP (amorphous calcium phosphate or Ca₃(PO₄)₂H₂O); DCP(dicalcium phosphate, monetite or CaHPO₄); tricalcium phosphate,including both α- and β-(Ca₃(PO₄)₂, tetracalcium phosphate (Ca₄(PO₄)₂O,etc. Calcium sources of interest include, but are not limited to:calcium carbonate (CaCO₃), calcium oxide (CaO), calcium hydroxide(Ca(OH)₂) and the like. Phosphate sources of interest include, but arenot limited to: Phosphoric acid (H₃PO₄), all soluble phosphates; MCPM(monocalcium phosphate monohydrate or Ca(H₂PO₄)₂.H₂O) and sodium analogsthereof, e.g., NaH₂PO₄, and the like.

The ratios or relative amounts of each of the disparate calcium and/orphosphate compounds in the dry reactant mixture is one that provides forthe desired calcium phosphate product upon combination with the settingfluid and subsequent setting. In many embodiments, the overall ratio(i.e., of all of the disparate calcium and/or phosphate compounds in thedry reactants) of calcium to phosphate in the dry reactants ranges fromabout 4:1 to 0.5:1, usually from about 2:1 to 1:1 and more usually fromabout 1.9:1 to 1.25:1.

The second component of the calcium phosphate cement compositions is asetting fluid. The setting fluid can be any of a variety of settingfluids known to those of skill in the art. Setting fluids include avariety of physiologically compatible fluids, including, but are notlimited to: water (including purified forms thereof), aqueous alkanolsolutions, e.g. glycerol, where the alkanol is present in minor amounts,preferably less than about 20 volume percent; pH buffered ornon-buffered solutions; solutions of an alkali metal hydroxide, acetate,phosphate or carbonate, particularly sodium, more particularly sodiumphosphate or carbonate, e.g., at a concentration in the range of about0.01 to about 2M, such as from about 0.05 to about 0.5M, and at a pH inthe range of about 6 to about 11, such as from about 7 to about 9,including from about 7 to about 7.5; and the like.

Of particular interest in certain embodiments is a silicate settingfluid, i.e., a setting fluid that is a solution of a soluble silicate.By solution of a soluble silicate is meant an aqueous solution in whicha silicate compound is dissolved and/or suspended. The silicate compoundmay be any compound that is physiologically compatible and is soluble inwater. By soluble in water is meant a concentration of at least about1%, usually at least about 2% and more usually at least about 5%, wherethe concentration of the silicate employed typically ranges from about0-0.1 to 20%, usually from about 0.01-5 to 15% and more usually fromabout 5 to 10%. Silicate setting fluids finding use with calciumphosphate cements are further described in U.S. Pat. Nos. 6,375,935 and6,719,933; the disclosures of which are herein incorporated byreference.

A variety of calcium phosphate cement compositions are known to those ofskill in the art. Cement compositions known to those of skill in the artand of interest include, but are not limited to, those described in U.S.Pat. Nos.: 6,027,742; 6,005,162; 5,997,624; 5,976,234; 5,968,253;5,962,028; 5,954,867; 5,900,254; 5,697,981; 5,695,729; 5,679,294;5,580,623; 5,545,254; 5,525,148; 5,281,265; 4,990,163; 4,497,075; and4,429,691; the disclosures of which are herein incorporated byreference.

Of particular interest in certain embodiments is the cement compositiondisclosed U.S. Pat. Nos. 6,375,935 and 6,719,933; the disclosures ofwhich are herein incorporated by reference.

In preparing such cements, suitable amounts of the dry reactants and thesetting fluid of the cement composition to be delivered to the targetsite are combined to produce a settable or flowable composition. Inother words, the ratio of the dry reactants to setting fluid (i.e. theliquid to solids ratio) is selected to provide for a “settable” or“flowable” composition, where by “settable” or “flowable” composition ismeant a composition that goes from a first non-solid (and alsonon-gaseous) state to a second, solid state after setting. In manyembodiments, the liquid to solids ratio is chosen to provide for aflowable composition that has a viscosity ranging from that of milk tothat of modeling clay. As such, the liquids to solids ratio employed inthe subject methods typically ranges from about 0.2 to 1.0, usually fromabout 0.3 to 0.6. Of particular interest in many embodiments are methodsthat produce a paste composition, where the liquid to solids ratioemployed in such methods typically ranges form about 0.25 to 0.5,usually from about 0.3 to 0.45.

The dry and liquid components are typically combined under agitation ormixing conditions, such that a homogenous composition is produced fromthe dry and liquid components. Mixing may be accomplished using anyconvenient means, including manual mixing as described in U.S. Pat. No.6,005,162 and automated mixing as described in WO 98/28068, thedisclosures of which are herein incorporated by reference. Also ofinterest is the device disclosed in U.S. Pat. No. 5,980,482, thedisclosure of which is herein incorporated by reference.

The temperature of the environment in which combination or mixing of thedry and liquid components takes place is sufficient to provide for aproduct that has desired setting and strength characteristics, andtypically ranges from about 0 to 50° C., usually from about 15 to 30° C.Mixing takes place for a period of time sufficient for the flowablecomposition to be produced, and generally takes place for a period oftime ranging from about 15 to 120 seconds, usually from about 15 to 90seconds and more usually from about 30 to 60 second.

The resultant settable compositions produced by the above-describedmethods are compositions that set into a biologically compatible, andoften resorbable and/or remodelable, product, where the product ischaracterized by including calcium phosphate molecules not present inthe initial reactants, i.e., that are the product of a chemical reactionamong the initial reactants.

The term flowable is meant to include paste-like and even clay-likecompositions, as well as more liquid compositions. As such, theviscosity time of the subject flowable compositions, defined as timeperiods under which the mixed composition injects through a standardLuer-lok fitting after mixing, typically ranges up to about 10 minutes;usually up to about 7 minutes, such as up to about 4 minutes. Ofparticular interest in many embodiments are paste compositions that havean injectable viscosity and inject in a time period ranging up to about5 minutes, such as about up to about 4 minutes. Pastes that staypaste-like for longer periods may be displaced by bleeding bone onceimplanted into the body, which create a blood interface between thecement and the bone prior to the cement hardening.

The compositions produced by the subject invention set into calciumphosphate mineral containing products. By “calcium phosphate mineralcontaining” product is meant a solid product that includes one or more,usually primarily one, calcium phosphate mineral. In many, embodiments,the calcium phosphate mineral is one that is generally poorlycrystalline, so as to be resorbable and, often, remodelable, over timewhen implanted into a physiologically site. The calcium to phosphateratio in the product may vary depending on particular reactants andamounts thereof employed to produce it, but typically ranges from about2:1 to 1.33:1, usually from about 1.8:1 to 1.4:1 and more usually fromabout 1:7:1 to 1.5:1. Of particular interest in many embodiments areapatitic products, which apatitic products have a calcium to phosphateratio ranging from about 2.0:1 to 1.25:1, including both hydroxyapatiteand calcium deficient analogs thereof, including carbonate substitutedhydroxyapatite (i.e. dahllite), etc. The subject paste-like compositionis, in many embodiments, one that is capable of setting into ahydroxyapatitic product, such as a carbonated hydroxyapatite, i.e.dahllite, having a carbonate substitution of from about 2 to about 10%,usually from about 2 to about 8% by weight of the final product.

The period of time required for the compositions to harden or “set” mayvary. By set is meant: the Gilmore Needle Test (ASTM C266-89), modifiedwith the cement submerged under 37° C. physiological saline. The settimes of the subject cements may range from about 30 seconds to 30minutes, such as from about 2 to 15 minutes and including from about 4to 12 minutes. In representative embodiments, the flowable compositionsets in a clinically relevant period of time. By clinically relevantperiod of time is meant that the paste-like composition sets in lessthan about 20 minutes, such as less than about 10 minutes and includingless than about 5 minutes, where the composition remains flowable for atleast about 1 minute, including at least about 2 minutes followingcombination or mixture of the precursor liquid and dry cementcomponents.

The compressive strength of the product into which the settable/flowablecomposition sets may vary significantly depending on the particularcomponents employed to produce it. Of particular interest in manyembodiments is a product that has a compressive strength sufficient forit to serve as at least a cancellous bone structural material. Bycancellous bone structural material is meant a material that can be usedas a cancellous bone substitute material as it is capable ofwithstanding the physiological compressive loads experienced bycompressive bone under at least normal physiological conditions. Assuch, the subject flowable paste-like material is one that sets into aproduct having a compressive strength of at least about 10, usually atleast about 25 and more usually at least about 50 MPa, as measured bythe assay described in Morgan, E F et al., 1997, Mechanical Propertiesof Carbonated Apatite Bone Mineral Substitute: Strength, Fracture andFatigue Behavior. J. Materials Science: Materials in Medicine. V. 8, pp559-570, where the compressive strength of the final apatitic productmay be as high as 60 MPa or higher. Inclusion of the silicate in thesetting liquid allows lower liquid to solids ratios to be employed whichresults in significantly higher compressive strengths. Compressivestrengths can be obtained that range as high as 100 to 200 MPa. Incertain embodiments, the resultant product has a tensile strength of atleast about 0.5 MPa, such as at least about 1 MPa, including at leastabout 5 MPa, at least about 10 MPa or even 20 Mpa or more, e.g., fromabout 0.5 to about 10 MPa, as determined by the tensile strength assayappearing in the Experimental Section, below.

In certain embodiments, the resultant product is stable in vivo forextended periods of time, by which is meant that it does not dissolve ordegrade (exclusive of the remodeling activity of osteoclasts) under invivo conditions, e.g., when implanted into a living being, for extendedperiods of time. In these embodiments, the resultant product may bestable for at least about 4 months, at least about 6 months, at leastabout 1 year or longer, e.g., 2.5 years, 5 years, etc. In certainembodiments, the resultant product is stable in vitro when placed in anaqueous environment for extended periods of time, by which is meant thatit does not dissolve or degrade in an aqueous environment, e.g., whenimmersed in water, for extended periods of time. In these embodiments,the resultant product may be stable for at least 2 weeks, e.g., at leastabout 1 month, including at least about 4 months, at least about 6months, at least about 1 year or longer, e.g., 2.5 years, 5 years, etc.The length of the time that the implant persists is determined by theextent to which it replaced by new bone via cell-mediated remodeling,which is primarily a stress-mediated process and thus dependent on thespecific anatomical site.

In many embodiments, the settable paste-like composition is capable ofsetting in a fluid environment, such as an in vivo environment at a bonerepair site. As such, the settable paste composition can set in a wetenvironment, e.g., one that is filled with blood and other physiologicalfluids. Therefore, the site to which the flowable composition isadministered during use need not be maintained in a dry state.

In certain embodiments, the cements may include imaging or “tracer”elements, e.g., radioopaque or radioopacifier elements, which providefor enhanced imaging of the cement during delivery, e.g., as visualizedby radiographic imaging techniques. Representative radiopaque particlesthat may find use include radiopaque materials selected from a groupconsisting of barium sulfate, zirconium dioxide, tantalum, tungsten,platinum, gold, silver, stainless steel and titanium. Representativetracer elements and protocols for imaging the same are described in U.S.Pat. Nos. 6,309,420 and 6,273,916; the disclosures of which are hereinincorporated by reference.

In certain embodiments, the cement may include a water-soluble contrastagent, as described in U.S. application Ser. No. 10/629,321; thedisclosure of which is herein incorporated by reference. Bywater-soluble contrast agent is meant an agent that readily dissolves inwater (i.e., is water-soluble), as defined above. In many embodiments,the water-soluble contrast agent is a water-soluble salt of aradio-opaque element, i.e., an element that is visible under standardimaging techniques and protocols employed by those of skill in the art,e.g., fluoroscopic X-ray imaging protocols, etc. The radio-opaqueelement is one that appears different from calcium when viewed usingsuch imaging techniques, where representative elements ofinterest-include, but are not limited to: barium, oxalate, zirconium,tantalum, tungsten and the like. In certain embodiments, the contrastagent is a salt of an element that is incorporated into a compound ofthe calcium phosphate product of the flowable composition produced bythe cement. For example, in certain embodiments the salt is a salt of anelement that is incorporated into an apatitic compound present in thecalcium phosphate product. Of particular interest are water-solublebarium salts, e.g., barium halides, including barium chloride, etc.

In certain embodiments, the cement may include an osteoclastogenicagent, as described in U.S. application Ser. No. 10/717,171; thedisclosure of which is herein incorporated by reference. Byosteoclastogenic agent is meant an agent that inducesosteoclastogenesis, i.e., causes differentiation of hematopoieticmonocyte/macrophage precursors into osteoclasts. In many embodiments,the osteoclastogenic agent is a modulator of the RANK mediatedosteoclastogenesis induction pathway. As such, the agent may modulatethe activity of one or more members of the RANK mediatedosteoclastogenesis induction pathway, e.g., TRAF6, NK-κB1, NF-κB2,c-fos, RANKL, etc. In many embodiments, the osteoclastogenic agent istypically an enhancer of the RANK mediated osteoclastogenic inductionpathway. In many embodiments, the osteoclastogenic agent is a ligand forthe RANK receptor. The RANK receptor is known and described in U.S. Pat.Nos. 6,537,763; 6,528,482; 6,479,635; and 6,017,729; the disclosures ofwhich are herein incorporated by reference.

In certain embodiments, the cement may include a barium apatiteparticulate composition in which the average particle size of thecollection, population or set of barium apatite particles thatcollectively make up the contrast agent composition is selected orchosen to impart a “peppered” appearance to the cement when imaged usingradiographic imaging protocols, e.g., via fluoroscopy. The averageparticle size of the barium apatite particulate composition ranges, incertain embodiments, from about 1 to about 1000μ, such as from about 50to about 500μ, including from about 200 to about 400μ. The amount ofparticulate contrast agent that is employed in a given application mayrange, in certain embodiments, from about 1% to about 50%, such as fromabout 5% to about 50%, including from about 10% to about 35%, where incertain embodiments these percentages are percentages by weight and inother embodiments these percentages are percentages by volume. Suchcompositions are further described in U.S. application Ser. No.10/851,766; the disclosure of which is herein incorporated by reference.

In certain embodiments, the cement compositions may be seeded with anyof a variety of cells. A “cell”, according to the present invention, isany preparation of living tissue, including primary tissue explants andpreparations thereof, isolated cells, cells lines (including transformedcells), and host cells. Preferably, autologous cells are employed, butxenogeneic, allogeneic, or syngeneic cells are also useful. As such, thecells can be obtained directly from a mammalian donor, e.g., a patient'sown cells, from a culture of cells from a donor, or from establishedcell culture lines. The mammal can be a mouse, rat, rabbit, guinea pig,hamster, cow, pig, horse, goat, sheep, cog, cat, and the mammal can be ahuman. Cells of the same species and preferably of the sameimmunological profile can be obtained by biopsy, either from the patientor a close relative. Where the cells are not autologous, it may bedesirable to administer immunosuppressive agents in order to minimizerejection. In preferred embodiments, such agents may be included withinthe seeded composition to ensure effective local concentrations of theagents and to minimize systemic effects of their administration. Thecells employed may be primary cells, explants, or cell lines, and may bedividing or non-dividing cells. Cells may be expanded ex-vivo prior tointroduction into the inventive cement compositions. Autologous cellsare preferably expanded in this way if a sufficient number of viablecells cannot be harvested from the host.

Any preparation of living cells may be use to seed the cementcomposition of the present invention. For example, cultured cells orisolated individual cells may be used. Alternatively or additionally,pieces of tissue, including tissue that has some internal structure, maybe used. The cells may be primary tissue explants and preparationsthereof, cell lines (including transformed cells), or host cells.

Any available methods may be employed to harvest, maintain, expand, andprepare cells for use in the present invention. Useful references thatdescribe such procedures include, for example, Freshney, Culture ofAnimal Cells: a Manual of Basic Technique, Alan R. Liss Inc., New York,N.Y., incorporated herein by reference.

The cement composition material of the invention is useful as a scaffoldfor production of hard or soft tissues. Tissue-producing or -degradingcells that may be incorporated into the material include, but are notlimited to, chondrocytes, osteocytes, osteoblasts, osteoclasts,mesenchymal stem cells, other bone- or cartilage-producing cells or celllines, fibroblasts, muscle cells, hepatocytes, parenchymal cells, cellsof intestinal origin, nerve cells, and skin cells.

Methods of isolating and culturing such tissue-producing or -degradingcells, and/or their precursors, are known in the art (see, for example,Vacanti et al., U.S. Pat. No. 5,041,138; Elgendy et al., Biomater.14:263, 1993; Laurencin et al., J. Biomed. Res. 27:963, 1993; Freed etal., J. Cell. Biochem. 51:257, 1993; Atala et al., J. Urol. 150:745,1993; Ishaug et al., J. Biomed. Mater. Res. 28:1445, 1994; Chu et al.,J. Biomed. Mater. Res. 29:1147, 1995; Thomson et al., J. Biomater. Sci.Polymer Edn. 7:23, 1995, each of which is incorporated by reference).

For example, mesenchymal stem cells, which can differentiate into avariety of mesenchymal or connective tissues (including, for example,adipose, osseous, cartilagenous, elastic, and fibrous connectivetissues), can be isolated, purified, and replicated according to knowntechniques (see Caplan et al., U.S. Pat. No. 5,486,359; Caplan et al.,U.S. Pat. No. 5,226,914; Dennis et al., Cell Transplantation 1:23, 1992,each of which is incorporated herein by reference). Such mesenchymalcells have been studied in association with tricalcium phosphate andhydroxyapatite carriers and have been found to be capable of successfuldifferentiation from within such carriers (see Caplan et al., U.S. Pat.No. 5,197,985, incorporated herein by reference). Similar procedures areemployed to direct mesenchymal cell differentiation within the cementmaterial of the present invention.

Of course, the present invention is not limited to the use oftissue-producing cells. Certain preferred embodiments of the inventionutilize such cells, primarily because the inventive material is so wellsuited to tissue-regeneration applications (particularly with thoseinvolving growth of bone and/or cartilage). Any cell may be seeded intothe material of the invention. In some cases, it will be desirable toinclude other cells in addition with tissue-producing cells.

Any convenient cell source may be employed. For example, where thematerial is seeded with stem cells, e.g., adult stem cells, mesenchymalstem cells, any convenient stem cell source may be employed. Stem cellsources of interest include bone marrow, cord blood, etc., which sourcemay be treated to enrich the target stem cell population of interest,e.g., fractionated, etc.

The cells that are seeded into the cement composition may be geneticallyengineered, for example to produce a protein or other factor that ituseful in the particular application. In preferred embodiments, cellsmay be engineered to produce molecules that impart resistance to hostimmune attack and rejection. The Fas-L and CR-1 genes are examples ofuseful such genes.

Generally, cells are introduced into the subject material of the presentinvention in vitro, although in vivo seeding approaches are employed insome circumstances. Cells are typically mixed with the cementcomposition prior to setting.

Any available method may be employed to introduce the cells into thecement composition material. For example, cells may be injected into theflowable cement composition (sometimes in combination with growthmedium), or maybe introduced by other means such as pressure, vacuum, orosmosis. Alternatively (or additionally), cells may be layered on theflowable cement composition. In certain embodiments, it may be desirableto manually mix or knead the cells with the material paste. Cells mayalso be introduced into the hydrated precursor in vivo simply by placingthe material in the body adjacent a source of desired cells. In somecases, it may be desirable to enhance such in vivo cell impregnation byincluding within the material an appropriate chemotactic factor,associative factor (i.e., a factor to which cells bind), or factor thatinduces differentiation of cells into the desired cell type.

As those of ordinary skill will readily appreciate, the number of cellsto be introduced into the inventive material will vary based on theintended application of the seeded material and on the type of cellused. Where dividing autologous cells are being introduced by injectioninto the hydrated precursor, use of 20,000-1,000,000 cells per cm3 areexpected to result in cellular proliferation and extracellular matrixformation within the material. Where non-dividing cells are employed,larger numbers of cells will generally be required. In those cases whereseeding is accomplished by host cell migration into the material invivo, exposure of the material to fluids containing cells (e.g.,bone-forming cells), or to tissue (e.g., bone) itself has proven to beeffective to seed the material with cells without the need forinoculation with a specified number of cells. The use of cells asdescribed above is further described in U.S. Pat. No. 6,139,578 and thereferences cited therein, the disclosures of which are hereinincorporated by reference.

Seeding a structural cement with plurlipotent cells according to theabove description results in stress induced cell differentiation of thepluripotent cells, e.g., into bone forming cells, i.e., osteoblasts. Assuch, the subject invention provides methods of differentiatingpluripotent cells into bone form cells via stress induction, wherein asufficient amount of pluripotent cells are seeded in a structural cementas described above, which is subsequently allowed to set and, uponsetting, results in stress induced differentiation of cells seededtherein as a result of mechanical forces applied to the set cementcomposition.

Delivery Through a Passageway of a Hard Tissue Securing Device

As summarized above, a feature of the subject methods is that the cementcomposition is delivered to the target bone site through the passagewayof the hard tissue defect securing device while a vibratory force isapplied to the securing device. In representative embodiments, a cementis employed in conjunction with securing hardware to achieve compositefixation. In composite fixation, the cement may be employed with one ormore types of hardware, e.g., screws, nails, plates, wires, etc. In suchembodiments, vibration may be applied to the cement via applyingvibratory force to the hardware during delivery to achieve a superiorcomposite fixation, e.g., in terms of better interface between thecement and hardware components of the composite fixation structure.

In representative embodiments, the hardware component(s) isdelivered/positioned first, followed by delivery of the cementcomponent, which cement component is delivered in conjunction withvibration according to the subject methods. The hard tissue securingdevice may be implanted at a target bone site using any convenientprocedure developed for that device. For example, following fractionreduction, a given securing device may be implanted at the target siteusing known protocols for that device, where such protocols may or mayinclude the use of manual and/or power driven tools, as is known in theart.

The term “vibratory force” is used to refer to vibration (i.e., anoscillating force) that is applied to a hard tissue securing device,where the nature of the vibratory force may vary depending on theparticular embodiment of the subject invention. Any convenientrepresentative vibratory force may be employed, where representativevibratory forces include, but are not limited to, sonic forces,mechanical forces, etc. The vibratory force may be characterized interms of frequency, such as cycles per second (Hertz or Hz), where incertain embodiments the vibratory force applied to an object during thesubject methods may have a frequency that ranges from about 0.1 to about100,000 Hz or higher, including from about 5.0 to about 100,000 Hz orhigher, e.g., from about 5.0 to about 50,000 Hz or higher, such as fromabout 10 to about 35,000 Hz, including from about 20 to about 20,000 Hz.In certain embodiments, the vibratory force has a frequency that issufficient to provide for the desired outcome, e.g., full delivery ofthe cement without application of significant backforce (as described ingreater detail below) but does not exceed about 10,000 Hz, and incertain embodiments does not exceed about 5000 Hz, and in certainembodiments does not exceed about 1000 Hz. Where the vibratory forceapplied to an object during the subject methods is a sonic force, theforce may be infrasonic or ultrasonic, or in the audible range. Thevibratory force may also be characterized in terms of its amplitude ormagnitude of vibration. By “amplitude” is meant the movement in anydirection. In representative embodiments, the amplitude of the appliedvibratory force will range from about 1 Angstrom to about 2 mm, such asfrom about 1 to about 500 microns, including from about 10 to 100microns. In certain embodiments, the amplitude of the applied vibratoryforce will range from about 1 Angstrom to about 1 mm, such as from about1 to about 100 microns, including from about 10 to 50 microns. Dependingon the application and desired nature of the vibratory force, thedirection or orientation of the vibration may vary, where representativeorientations include, but are not limited to: circular, unidirectional,random, etc. In some instance, the vibration parameters, e.g., frequencyand/or amplitude, may be varied over the course or duration of thevibration usage, as may be desired depending on the particularapplication being performed.

The vibratory force may be applied directly or indirectly to the hardtissue securing device in a variety of different ways. For example, theforce may be applied directly to the hard tissue securing device using amechanical application element, a sonic application element, etc., asdescribed in greater detail below. Alternatively, the force may beapplied indirectly to the hard tissue securing device, e.g., thevibratory force may be applied to a delivery element that is associatedwith the securing device in a force transfer relationship. For example,the delivery element, e.g., cannula, syringe, etc., may be configured tomate with the entry port of the securing device passageway, and avibratory force applied to the delivery element, where the appliedvibratory force is transferred to the securing device because of theforce transfer relation of the delivery element mated with the securingdevice.

In a representative embodiment, composite fixation according to thepresent invention may employ the use of what is known in the art ascannulated screws, i.e., screws with hollow centers which have entry andexit ports through which material can be introduced and removed from thehollow center of the screw, as reviewed above. In these embodiments, thescrew(s) may be placed or positioned in the subject first, e.g., bydelivery over a guidewire, according to methods known in the art.Following placement of the screw, the cement is delivered to the site,e.g., through the screw, in conjunction with vibration, where thevibratory force may be applied to the screw directly or indirectly,e.g., to a delivery device mated with the screw in a force transferrelationship and/or the cannulated screw, etc.

In representative embodiments, the amount of vibratory force that isapplied to the cement, e.g., through application to the deliveryelement, is typically sufficient to provide for highly controlledpenetration of the cement through cancellous bone tissue. By “highlycontrolled penetration” is meant penetration of the cement throughcancellous bone tissue in manner that can be stopped at substantiallythe same time as cessation of vibration, such that when vibration stops,the cement no longer moves further into the cancellous tissue, and anymovement of the cement into the cancellous tissues continues for no morethan about 5 seconds, such as no more than about 1 to about 3 seconds.

A feature of certain embodiments of the subject methods is that thecement is delivered in manner that provides for highly controlledpenetration without the use of significant back-pressure on the cement.As such, any pressure applied to the cement during delivery does notexceed about 100 psi, and is between about 1 and 100 psi in certainembodiments. In certain of these embodiments, a negative pressure may bepresent at the target delivery site, which negative pressure enhancesentry of the cement composition to the target site. The negativepressure may be produced using any convenient protocol, e.g., the targetsite preparation protocol described above. Where a negative pressure ispresent at the target delivery site, the negative pressure may rangefrom about 1 to about 1000 psi, including from about 10 to about 100psi.

In representative embodiments, the cement is delivered such that itmixes with marrow etc., present at the target site, to provide acell-seeded cement, as described above.

Where desired, vibration may also be employed at one or more pointsduring a given orthopedic cement protocol. Typically, orthopedic cementprotocols at least include, in addition to the delivery step: cementpreparation, target site preparation, and optionally post deliverycement modification. Representative additional points at which vibrationmay be employed include, but are not limited to: cement preparation;target site preparation; and post delivery modification of the deliveredcement. Each of these different representative times or points at whichvibration may be employed is now reviewed separately in greater detail.

In certain embodiments of the subject invention, vibration is also usedin conjunction with at least the preparation of an orthopedic cement. Byused in conjunction with the preparation of an orthopedic cement ismeant that vibration is employed at some point during the period inwhich the cement precursors of the cement, e.g., liquid and solidreagents or cement components, are combined to produce a flowable cementproduct composition. With many orthopedic cements of interest, dry andliquid precursors, e.g., a powder and setting liquid, are combined to aproduce a flowable cement composition product that, over time, sets intoa solid material. In certain embodiments of the subject invention,vibration is employed by applying a vibratory force, e.g., sonic ormechanical, to the precursors of the flowable composition, e.g., duringmixing of the precursors. For example, in certain representativeembodiments, vibration may be applied to the container or vessel inwhich the flowable cement composition is prepared, and thereby appliedto the flowable cement composition as it is being prepared.

In certain of these representative embodiments, the vibratory force thatis applied to the cement may have a frequency ranging from about 0.1 Hzto about 100,000 Hz, such as from about 5 Hz to about 50,000 Hz,including from about 100 Hz to about 5000 Hz, and an amplitude rangingfrom about 1 angstrom to about 5 mm, such as from about 1 micron toabout 1 mm, including from about 10 micron to about 500 micron. Also ofinterest are the ranges provided above.

The vibratory force may be applied to the cement components for theduration of the preparatory time or for a portion thereof, e.g., whilethe initial components are combined, while additives are combined withthe product of mixing of the initial components, etc. In certainrepresentative embodiments, vibration is applied for a duration rangingfrom about 1 sec to about 10 minutes, such as from about 10 sec to about5 minutes, including from about 15 sec to about 1 minute and in certainembodiments a duration ranging from about 1 sec to about 5 minutes, suchas from about 10 sec to about 1 minute, including from about 15 sec toabout 30 sec.

In certain embodiments, vibration is also employed in conjunction withat least preparation of the target bone site. In the subject methods,the target bone site may be any of a variety of different bone sites. Inmany embodiments, the target bone site is an interior target bone site,e.g., an interior region of a bone, as a cancellous domain bounded bycortical walls. Often, the target bone site is made up of cancelloustissue, into which it is desired to penetrate the orthopedic cement toproduce a cancellous bone/cement composite structure. Representativecancellous bone target sites of interest include, but are not limitedto, those found in: vertebral body sites, femur sites, proximal humerussites, tibial plateau sites, calcaneous sites, distal radius sites, andthe like.

In these embodiments, vibration may be applied to the target bone siteusing any convenient protocol, depending on the desired outcome of theuse vibration in target bone site preparation. For example, in certainembodiments, preparation of the target bone site may include removal ofmarrow and/or other materials from the bone site, e.g., the methods mayinclude a marrow or hematoma removal step, where material, e.g., marrow,hematoma, at the target site is removed, e.g., before and/or duringdelivery of the cement composition, so as to further enhance penetrationof the cement into the target site. For example, the marrow may beremoved by aspiration from the target bone site. More specifically,marrow may be aspirated from one side of the target site before or ascement is introduced into the other side. In these embodiments, avibratory force may be applied to the target bone site to enhance therate and/or efficiency of marrow, e.g., fatty marrow, removal.

In certain of these representative embodiments, the vibratory force thatis applied to the target bone site may have a frequency ranging fromabout 1 Hz to about 100,000 Hz, such as from about 10 Hz to about 10,000Hz, including from about 100 Hz to about 1000 Hz, and an amplituderanging from about 1 Angstrom to about 5 mm, such as from about 1 micronto about 100 micron, including from about 5 micron to about 50 micron.In certain representative embodiments, vibration is applied for aduration ranging from about 0.1 sec to about 20 minutes (e.g., fromabout 0.1 sec to about 10 minutes), such as from about 1 sec to about 10minutes (e.g., from about 1 sec to about 5 minutes), including fromabout 10 second to about 5 minutes (e.g., from about 10 seconds to about1 minute). Also of interest are the ranges provided above.

In certain embodiments, vibration may be also employed in conjunctionwith post delivery cement modification, e.g., to modulate (for exampleenhance or impede) the rate of setting of the cement, as desired for aparticular application. By selecting the appropriate type, duration andtiming of vibratory force, the rate of setting of the cement can bemodulated, e.g., increased or decreased, as desired. For example, incertain embodiments, following application or placement of an amount ofa cement composition to a target bone site, it may be desirable todecrease or slow the rate at which the cement sets or hardens. Forexample, a vibratory force may be applied to the cement compositionplaced or positioned at the target bone site, e.g., to slow cementsetting and provide longer time to is shape or model the positionedcement composition. For example, in certain embodiments, the cementcomposition, following placement, may initially set into a firstconfiguration. A vibratory force may be applied to the cement in thisfirst configuration in order to modify it to a second, more desirableconfiguration. In this manner, the configuration or shape of thepositioned or placed cement composition may be fined tuned or tailoredto achieve optimal results in a given application. In yet otherembodiments, vibration may be applied to further assist the cement inpenetrating into space adjacent to the direct site of introduction,e.g., through the cancellous structure of a vertebral body beyond theexact site of implantation or delivery.

In these embodiments where it is desired to slow or impede the rate ofcement setting, e.g., by at least about 2-fold, such as by at leastabout 5-fold, including by at least about 10-fold, the vibratory forcethat is applied to the delivered cement composition may have a frequencyranging from about 1 to about 100,000 Hz, such as from about 10 to about10,000 Hz, including from about 100 Hz to about 1000 Hz, and anamplitude ranging from about 1 Angstrom to about 5 mm, such as fromabout 1 micron to about 100 micron, including from about 5 micron toabout 50 micron. In certain representative embodiments, vibration isapplied for a duration ranging from about 0.1 sec to about 10 minutes,such as from about 1 sec to about 5 minutes, including from s about 10sec to about 1 minute. Also of interest are the ranges provided above.

In yet other embodiments, a vibratory force is applied that enhances oraccelerates the rate of setting of the cement, e.g., by at least about2-fold, such as by at least about 5-fold, including by at least about10-fold. In certain of these representative embodiments, the vibratoryforce that is applied to the delivered cement may have a frequencyranging from about 1 to about 100,000 Hz, such as from about 10 Hz toabout 10,000 Hz, including from about 100 Hz to about 1000 Hz, and anamplitude ranging from about 1 Angstrom to about 5 mm, such as fromabout 1 micron to about 100 micron, including from about 5 micron toabout 50 micron. In certain representative embodiments, vibration isapplied for a duration ranging from about 0.1 sec to about 10 minutes,such as from about 1 sec to about 5 minute, including from about 10 secto about 1 minute. Also of interest are the ranges provided above.

In certain embodiments, the settable cement composition is prepared at alocation apart from the delivery element, e.g., syringe and needle. Forexample, the cement may be prepared in a mortar and pestle and thenintroduced into the delivery element for placement at the target site.Alternatively, the cement may be prepared in pouch or analogousstructure, e.g., in its initial packaging (as described in U.S. Pat. No.6,375,935; the disclosure of which is herein incorporated by reference).In yet other embodiments, the cement is prepared in the deliveryelement, e.g., syringe, as it is being vibrated according to the presentinvention, where the vibration of the delivery element provides therequisite agitation to combine the liquid and solid components of thecement. As such, the liquid and solid components are introducedseparately into the delivery element, and vibration of the deliveryelement not only provides for delivery of the cement to the target sitein a manner according to the invention (and described above) but alsoagitates or mixes the liquid and solid components to produce theflowable composition. In these latter embodiments, one may employ adelivery element that is preloaded with the liquid and solid components,where the components are separated by a frangible barrier that, uponagitation or other convenient trigger, is broken to allow mixing of thesolid and liquid components, as desired.

Utility

The subject methods as described above find use in applications where itis desired to, use an orthopedic cement and an implantable securingdevice for composite fixation at a physiological site of interest, suchas in dental, craniomaxillofacial and orthopedic applications, as wellas other application in which a bone defect filling composition isemployed. In orthopedic applications, the cement will generally beprepared and introduced through a passageway of a securing device thathas been implanted at a bone repair site, such as a reduced fracturebone site that includes cancellous bone. The subject methods findparticular use in those applications where it is desired to introduce acement into a cancellous bone target site in a manner such that thecement penetrates the cancellous bone to produce a cancellousbone/cement composite structure, and a strong interface with thesecuring device employed in the composite fixation.

Representative orthopedic applications in which the invention findsparticular use include the treatment of fractures and/or implantaugmentation, in mammalian hosts, particularly humans. In such fracturetreatment applications, the fracture may or may not be reduced first, asdesired or convenient. Following any fracture reduction and implantationof the securing device, a settable structural material is introducedthrough the passageway of the securing device into the cancellous tissuein the fracture region using the delivery methods described above.Specific dental, craniomaxillofacial and orthopedic indications in whichthe subject invention finds use include, but are not limited to, thosedescribed in U.S. Pat. No. 6,149,655, the disclosure of which is hereinincorporated by reference.

Systems

Also provided are systems that find use in practicing the methods of thesubject invention, as described above. In representative embodiments,the subject systems at least include: a securing device, e.g., a screw,plate, nail, rod, wire, etc., a cement handling element, e.g., mixingelement, delivery element, shaping element, etc.; and a vibratoryelement for applying a vibratory force to the delivery device, eitherdirectly or indirectly, as described above.

In certain embodiments, the delivery device and hardware are configuredsuch that the delivery device can mate to the passageway of the hardwaresuch that the hardware and delivery device are in a force transferrelationship. In these embodiments, the hardware and/or the deliverydevice may be modified to provide for the force transfer relations. Forexample, the systems of these embodiments may include at least: (a) adelivery device for the cement; and (b) a vibratory element forindirectly vibrating the securing device during delivery, e.g., byapplying vibratory force directly to the delivery device. The deliverydevice in many of these representative embodiments includes a flowablecomposition introduction element, such as a syringe and needle, wherethis element is typically attached to a reservoir of the cementcomposition, e.g., a syringe body filled with the cement.

A feature of certain of these embodiments is that the delivery deviceincludes an element that provides for a force transfer relationship withthe hard tissue securing device, e.g., a mating interface at the end ofthe delivery device that mates with the entry into the passageway of thesecuring device. Representative mating interfaces of interest for thiselement include, but are not limited to: luer locks, nipple structures,nozzels, thread structures, etc., that provide for stable association ofthe delivery device to the hardware. For example, a cannulated screw maybe threaded at one end for mating in a secure cement transferrelationship with a threaded end of a delivery element, such that thedelivery element can be secured to the end of the cannulated screw.

In these representative embodiments, the vibratory element may be anyconvenient means for vibrating the cement composition as it isintroduced by the delivery device to the target bone site. Arepresentative type of vibratory element that may be included in thesubject systems is a device that vibrates a needle or analogousstructure of a cement delivery device.

A representative device that is capable of vibrating a needle to delivera cement to a target site according to the present invention is depictedin various views in FIGS. 1 to 6. As can be seen in FIG. 1, thisrepresentative vibratory element 10 is made up of a pneumatically drivenvibrating disc 12 that includes a needle holder 14. When a needle of acement delivery device (not shown) is present in the needle holder,vibration in the disc is transferred to the needle which, in turn, istransferred to the cement composition being delivered thereby. Alsoshown is handle 16 (which also serves as an air intake conduit) andexhaust piece 18, through which air leaves the device. The vibratoryelement is dimensioned for easy use with a cement delivery element, andtherefore typically ranges in length X from about 0.25 to 2.5 ft, suchas from about 0.5 to about 1.5 feet, including from about 0.75 to about1 feet; and a height Y ranging from about 0.5 to 12 in, such as fromabout 1 to about 10 inches, including from about 1 to about 5 inches.

FIG. 2 provides another view of the device shown in FIG. 1, where theair flow through the device is depicted. In the device shown in FIG. 2,airflow generated by an air compressor 20 flows through the handle 16and into an air intake port of a race or track 19 present inside of thedisc. Air flows around the race and out the exhaust 18. Force producedby the air flow propels a steel bearing or ball (not shown) around thetrack at a high frequency. Momentum of the ball creates up and downvibration in the direction of arrow 22 that is transferred to aneedle-holder and ultimately the material being dispensed by the needle.Vibration facilitates the flow of cement by reducing particle adhesionand literally “pushing” the cement downward.

FIG. 3 provides another view of the disc 12 of the device. Shown in thedepiction of FIG. 3, disc 12 includes race or track 19 around which ball17 moves, as driven by air flowing from the intake 11 to the exhaust 13.

FIG. 4 provides a cross-sectional view of a representative race 40 and aball 17 inside of the race. The race 40 has an angled end 41 along whichthe ball travels as it moves along the race.

FIGS. 5A and 5B provide detailed views of the handle element 16. Asshown in FIG. 5A, handle 16 includes an internal air flow passageway 51for airflow from an external compressor to the race of the disccomponent 12. At one of the handle 16 is threaded disc attachmentelement 52, while at the other end is threaded receiving element 53 forattachment to an external air source, e.g., compressor. FIG. 5B providesan angled view of the handle shown in FIG. 5A.

FIGS. 6A to 6D provide various views of needle holder 14. FIG. 6Aprovides a side view of needle holder 14 showing a through-all hole 61which is cut and countersunk to fit a delivery needle (not shown). Alsoshown is threaded disc attachment element 62, and through-all hole 63for set screw. FIG. 6B provides a front view of the needle 14 showingthe through-all hole 63 for the set screw 64, where hole 63 intersectshole 61. FIG. 6C shows a delivery element 65 positioned in hole 61 andheld in place by set screw 64 positioned in hole 63. FIG. 6D provides anangled view of needle holder 14 holding a delivery needle 65.

FIG. 7 provides a view of an alternative vibratory device for impartingvibration to a delivery cannula, and in doing so to a cement beingdelivered by the cannula. In FIG. 7, device 70 is a hand held device forimparting a vibratory force to a cement delivery cannula. Device 70includes a housing 72 and compressed air supply 74. Compressed airsupply 74 drives Variable RPM air spindle 76. Spindle 76 rotateseccentric mass 78 having a geometry selected to provide for the desiredvibratory force. At the distal end of device 70 is cannula interface 79that interfaces with and holds cannula 80 as shown.

In certain embodiments of the subject systems, the cement deliverydevice and the vibratory element are distinct from each other, i.e.,they are separate devices. In yet other embodiments, the delivery deviceand vibratory element are found on a single integrated device orinstrument.

In certain embodiments, the subject systems further include a cementcomposition or components thereof, as described above, where thecomponents may or may not be combined into a flowable composition.

Devices

Also provided are cement delivery devices that include a vibratoryelement which is capable of vibrating a cement composition while it isbeing delivered, as described above. The vibrating element may beintegral or separate from the other components of the device. Forexample, devices that include a vibrating cement delivery needle, wherethe vibration of the needle is provided by an element integral to thedelivery device, are provided by the subject invention.

Kits

Also provided are kits for use in practicing the subject methods. Thekits at least include one or more vibratory elements, as describedabove, for applying vibration to a hardware securing device, eitherdirectly or indirectly as described above. In representativeembodiments, the kits also include a delivery device for delivering acement composition, where in certain embodiments the delivery device andvibratory element may integrated into a single instrument, such thatthey are components of the same device.

In certain embodiments, the kits further include a calcium phosphatecement, where the dry and liquid components may be present in separatecontainers in the kit, or some of the components may be combined intoone container, such as a kit wherein the dry components are present in afirst portion and the liquid components are present in a second portion,where the portions are contained so they may or may not be present in acombined configuration, as described in U.S. Pat. No. 6,149,655, thedisclosure of which is herein incorporated by reference. In certainembodiments, the kits may include two or more setting fluids indifferent concentrations, e.g., where one wishes to provide a kit withflexibility with respect to the nature of the setting fluid that isprepared therefrom. For example, a kit may include two more differentphosphate-silicate solutions that differ from each other with respect totheir silicate and/or phosphate components. Alternatively, the kit mayinclude to or more different, separate phosphate and/or silicatesolutions that differ from each other in terms is of concentration andthat are mixed upon use of the kit as desired to obtain a desiredsetting fluid. As mentioned above, the kit components may be present inseparate containers. Alternatively, the components may be present as apackaged element, such as those described above.

In certain embodiments, the kits further include a polymeric cement,where the dry and liquid components may be present in separatecontainers in the kit, or some of the components may be combined intoone container, such as a kit wherein the dry components are present in afirst portion and the liquid components are present in a second portion,where the portions are contained so they may or may not be present in acombined configuration, as described in U.S. Pat. No. 6,149,655, thedisclosure of which is herein incorporated by reference. As mentionedabove, the kit components may be present in separate containers.Alternatively, the components may be present as a packaged element, suchas those described above.

In addition to above-mentioned components, the subject kits typicallyfurther include instructions for using the components of the kit topractice the subject methods. The instructions for practicing thesubject methods are generally recorded on a suitable recording medium.For example, the instructions may be printed on a substrate, such aspaper or plastic, etc. As such, the instructions may be present in thekits as a package insert, in the labeling of the container of the kit orcomponents thereof (i.e., associated with the packaging or subpackaging)etc. In other embodiments, the instructions are present as an electronicstorage data file present on a suitable computer readable storagemedium, e.g. CD-ROM, diskette, etc. In yet other embodiments, the actualinstructions are not present in the kit, but means for obtaining theinstructions from a remote source, e.g. via the internet, are provided.An example of this embodiment is a kit that includes a web address wherethe instructions can be viewed and/or from which the instructions can bedownloaded. As with the instructions, this means for obtaining theinstructions is recorded on a suitable substrate.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Accordingly, the preceding merely illustrates the principles of theinvention. It will be appreciated that those skilled in the art will beable to devise various arrangements which, although not explicitlydescribed or shown herein, embody the principles of the invention andare included within its spirit and scope. Furthermore, all examples andconditional language recited herein are principally intended to aid thereader in understanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentinvention, therefore, is not intended to be limited to the exemplaryembodiments shown and described herein. Rather, the scope and spirit ofpresent invention is embodied by the appended claims.

What is claimed is:
 1. A system for introducing an orthopedic cement toa target bone site, said system comprising: (a) an orthopedic calciumphosphate cement composition; (b) a cannulated hard tissue securingdevice that comprises: an elongated body, an internal passageway throughwhich the orthopedic calcium phosphate cement composition is driven, andthreading at an end of the elongated body; and (c) a cement deliverydevice comprising: (i) a needle, wherein a distal end of the needlecomprises threads that mate with the threading of the cannulated hardtissue securing device such that the orthopedic calcium phosphate cementcomposition passes through the needle and into the internal passagewayof the cannulated hard tissue securing device, (ii) a needle holder thatsecures the needle to the cement delivery device, and (ii) a vibratoryelement connected to the needle holder that vibrates the needle via apneumatically driven vibrating disc, wherein the vibration facilitatespushing the orthopedic calcium phosphate cement composition through theneedle into the internal passageway of the cannulated hard tissuesecuring device.
 2. The system according to claim 1, wherein thecannulated hard tissue securing device is a screw.
 3. The systemaccording to claim 1, wherein the cannulated hard tissue securing deviceis a plate.
 4. The system according to claim 1, wherein the cannulatedhard tissue securing device is a nail.
 5. The system according to claim1, wherein the vibration is sufficient to provide highly controlledpenetration of the cement into the target bone site without use ofsubstantial pressure.
 6. The system according to claim 1, wherein thepassageway is a channel bounded on all sides, with an inlet at a firstend of the cannulated hard tissue securing device and an exit at asecond end of the cannulated hard tissue securing device.
 7. The systemaccording to claim 1, wherein the vibration changes a shape of thecement composition after the cement composition is received into thetarget bone site.
 8. The system according to claim 1, wherein thevibration modulates a rate of setting of the cement composition.
 9. Thesystem according to claim 8, wherein the vibration causes the cementcomposition to take more time to set as compared to a length of timethat the cement composition would have taken to set had the vibrationnot been applied.
 10. The system according to claim 8, wherein thevibration causes the cement composition to take less time to set ascompared to a length of time that the cement composition would havetaken to set had the vibration not been applied.
 11. A kit comprising:(a) an orthopedic calcium phosphate cement composition; (b) a cannulatedhard tissue securing device that comprises: an elongated body, aninternal passageway through which the orthopedic calcium phosphatecement composition is driven, and threading at an end of the elongatedbody; and (c) a cement delivery device comprising: (i) a needle, whereina distal end of the needle comprises threads that mate with thethreading of the cannulated hard tissue securing device such that theorthopedic calcium phosphate cement composition passes through theneedle and into the internal passageway of the cannulated hard tissuesecuring device, (ii) a needle holder that secures the needle to thecement delivery device, and (ii) a vibratory element connected to theneedle holder that vibrates the needle via a pneumatically drivenvibrating disc, wherein the vibration facilitates pushing the orthopediccalcium phosphate cement composition through the needle into theinternal passageway of the cannulated hard tissue securing device. 12.The kit according to claim 11, wherein the vibration changes a shape ofthe cement composition after the cement composition is received into atarget bone site.
 13. The kit according to claim 11, wherein thevibration modulates a rate of setting of the cement composition.
 14. Thekit according to claim 13, wherein the vibration causes the cementcomposition to take more time to set as compared to a length of timethat the cement composition would have taken to set had the vibrationnot been applied.
 15. The kit according to claim 14, wherein thevibration causes the cement composition to take less time to set ascompared to a length of time that the cement composition would havetaken to set had the vibration not been applied.